1-formyl-2-alpha-(2-acyloxy-2-propylmercapto)-3 alpha-n-acyl-aminoazetidin-4-ones and process for their preparation

ABSTRACT

1 - R2 - 2A - (2 - ACYLOXY-2-PROPYLMERCAPTO)-3A-N-ACAMINO-AZETIDINE-4-ONES OF FORMULA   1-R2,3-(AC-NH-),4-(R1-COO-C(-CH3)2-S-)AZETIDIN-2-ONE   WHEREIN AC REPRESENTS THE ACYL RESIDUE OF AN ORGANIC ACID, R1 REPRESENTS AN ORGANIC RESIDUE AND R2 REPRESENTS A HYDROGEN ATOM OF A FORMYL GROUP, HAVE ANTIBACTERIAL PROPERTIES; THEY ARE PRIMARILY USEFUL AS INTERMEDIATES.

United States Patent O 3,711,464 1 FORMYL 2 ALPHA-(Z-ACYLOXY-Z-PROPYL- MERCAPTO) 3 ALPHA N ACYL-AMINO- AZETlDIN-4-ONES AND PROCESS FOR THEIR PREPARATION Karl Heusler, Basel, Switzerland, and Robert Burns Woodward, Cambridge, Mass., assignors to Ciba-Geigy Corporation No Drawing. Filed July 18, 1969, Ser. No. 843,204 Claims priority, application Switzerland, July 23, 1968, 10,998/68; Dec. 11, 1968, 18,507/68 Int. Cl. C07d 25/02 U.S. Cl. 260-239 A 9 Claims ABSTRACT OF THE DISCLOSURE 1 R 2a (2 acyloxy-2-propylmercapto)-3u-N-Acamino-azetidine-4-ones of formula wherein Ac represents the acyl residue of an organic acid, R represents an organic residue and R represents a hydrogen atom or a formyl group, have antibacterial properties; they are primarily useful as intermediates.

SUMMARY OF THE INVENTION The present invention relates to acyloxyalkylmercapto compounds, especially l-R -2a.-(2-acyloxy-2-propylmercapto)-3a-N-Ac-amino-azetidin-4-ones of formula wherein Ac represents the acyl residue of an organic acid, R represents an organic residue and R represents a hydrogen atom or a formyl group. The compounds are useful as antibacterial agents, primarily as intermediates for the manufacture of pharmacologically active compounds having paricularly the 7-amino-cephalosporanic acid structure.

PREFERRED EMBODIMENTS OF THE INVENTION 3,711,464 Patented Jan. 16, 1973 of an aliphatic carboxylic acid, which term also includes formic acid, is an alkyl, alkenyl or alkinyl radical, especially a lower alkyl or lower alkenyl residue, as Well as also a lower alkynyl radical, which can, for example, contain up to 7, preferably up to 4, carbon atoms. Such radicals can optionally be monosubstituted, disubstituted or polysub'stituted by functional groups, for example, by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto or optionally substituted phenylmercapto or phenyl-lower alkylmercapto, lower alkoxy-carbonyloxy or lower alkanoyloxy groups, as well as halogen atoms, and furthermore by nitro groups, optionally substituted amino groups, acyl, such as lower alkanoyl groups, or optionally functionally modified carboxyl groups, such as carbo-lower alkoxy, optionally N- substituted carbamoyl or cyano groups.

An optionally substituted cycloaliphatic or cycloaliphatic-aliphatic radical R which also can represent a cycloaliphatic or cycloaliphatic-aliphatic radical of a corresponding carboxylic acid is, for example, a monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl group or cycloalkylor cycloalkenyl-lower alkyl or -lower alkenyl group, wherein a cycloalkyl radical, for example, contains up to 12, such as 3-8, preferably 3-6, ring carbon atoms, while a cycloalkenyl radical can, for example, contain up to 12, such as 3-8, especially 5-8, preferably 5 or 6, ring carbon atoms, as well as 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic radical can, for example, contain up to 7, preferably up to 4, carbon atoms. The above cycloaliphatic or cycloaliphaticaliphatic radicals can, if desired, be monosubstituted, disubstituted or polysub'stituted, for example, by optionally substituted aliphatic hydrocarbon radicals, such as, for example, the optionally substituted lower alkyl groups mentioned above, or, for example, like the abovementioned aliphatic hydrocarbon radicals, by functional groups.

An optionally substituted aromatic hydrocarbon radical R which can also represent the aromatic radical of a corresponding carboxylic acid is, for example, a monocyclic, bicyclic or polycyclic aromatic hydrocarbon radical, especially a phenyl radical, as well as a biphenylyl or naphthyl radical, which can optionally be monosubstituted, disubstituted or polysubstituted, for example, like the above mentioned aliphatic and cycloaliphatic hydrocarbon radical.

An optionally substituted aralipha-tic hydrocarbon radical R which also represent the araliphatic radical in an araliphatic carboxylic acid is, for example an optionally substituted aliphatic hydrocarbon radical which, for example, possesses up to 3 optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon radicals, and primarly represents a phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl radical, such radicals containing, for example, 1-3 phenyl groups and optionally being monosubstituted, disubstituted or polysubstituted in the aromatic and/or aliphatic portion, for example, like the abovementioned aliphatic and cycloaliphatic radicals.

Heterocyclic radicals in heterocyclic or heterocyclicaliphatic radicals R which also can represent the corresponding radical in heterocyclic or heterocyclic-aliphatic carboxylic acid, are especially monocyclic, as well as bicyclic or polycyclic, azacyclic, thiacyclic, oxacyclic, thiazacyclic, oxazacyclic or diazacyclic radicals of aromatic character which can optionally be monosubstituted, disubstituted or polysubstituted, for example, like the abovementioned cycloaliphatic radicals. The aliphatic portion in heterocyclic-aliphatic radicals has, for example, the

significance given for the corresponding cycloaliphaticaliphatic or araliphatic radicals.

The acyl radical of a carbonic acid semi-derivative is preferably the acyl radical of a corresponding half-ester, wherein the esterifying organic radical represents an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of a lower alkyl half-ester of carbonic acid which is optionally substituted, preferably in the a-position, as well as in the lit-position (that is to say a carbo-lower alkoxy radical which is optionally substituted in the lower alkyl portion, preferably in the a-, as well as in the B-position), as well as a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyllower alkyl portion, respectively (that is to say a carbolower alkenyloxy, carbo-cycloalkoxy, carbo-phenyloxy or canbon-phenyl-lower alkoxy radical which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl portion, respectively). Acyl radicals of a carbonic acid half-ester are furthermore corresponding radicals of lower alkyl half-esters of carbonic acid, in which the lower alkyl portion contains a heterocyclic group, for example, one of the above mentioned heterocyclic groups of aromatic character, the lowr alkyl radical and the heterocyclic group being optionally substituted. Such acyl radicals are carbo-lower alkoxy groups which are optionally substituted in the lower alkyl portion and which contain an optionally substituted heterocyclic group of aromatic character in the lower alkyl radical.

A lower alkyl radical is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl or tert.- butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl group, while a lower alkenyl radical can, for example, be a vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl group, and a lower alkynyl radical, for example, a propargyl or Z-butynyl group.

A cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl group, and a cycloalkenyl group is, for example, a 2- or 3-cyclopentyl, 1-, 2- or 3-cyclohexenyl or 3-cycloheptenyl, as well as a 2-cyclopropenyl group. A cycloalkyl-lower alkyl or -lower alkenyl radical is, for example, a cyclopropyl-, cyclopentyl-, cyclohexyl-or cycloheptyl-methyl, -l,l-ethyl or 1,2-ethyl, -l,1-propyl, -1,2- propyl or 1,3 propyl, -vinyl or -allyl-group, While a cycloalkenyl-lower alkyl or -lower alkeny group represents, for example, a l-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenylor 1-, 2- or '3-cycloheptenyl-methyl -1,3-ethyl or -l,2-ethyl, -1,1-propyl, -1,2-propyl or -l,3-propyl, -vinyl or -allyl group.

A naphthyl radical is a 1- or 2-naphthy1 radical, while a biphenylyl group represents, for example, a 44biphenylyl radical.

A phenyl-lower alkyl or phenyl-lower alkenyl radical is, for example, a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3- phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.

Heterocyclic radicals are, for example, monocyclic, monoazacyclic, monothiacyclic or monooxacyclic radicals of aromatic character, such as pyridyl, for example, 2- pyridyl, 3-pyridyl or 4-pyridyl radicals, thienyl, for example, 2-thienyl radicals, or furyl, for example, 2-furyl radicals, or bicyclic monoazacyclic radicals of aromatic character, such as quinolinyl, for example, 2-quinolinyl or 4-quinolinyl radicals, or isoquinolinyl, for example, l-isoquinolinyl radicals, or monocyclic thiazacyclic or oxazacyclic as well as diazacyclic radicals of aromatic charater, such as oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, as well as pyrimidinyl radicals. Heterocyclic-aliphatic radicals are lower alkyl or lower alkenyl radicals containirg heterocyclic radicals, especially those mentioned a ove.

By etherified hydroxyl groups there are primarily to be understood lower alkoxy, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec.- butyloxy, tert.-butyloxy, n-pentyloxy or tert.-pentyloxy groups, as well as substiuted lower alkoxy, such as halogeno-lower alkoxy, especially 2-halogeno-lower alkoxy, for example, 2,2,2-trichloroethoxy or 2-iodoethoxy groups, furthermore lower alkenyloxy, for example, vinyloxy or allyloxy groups, lower alkylenedioxy, for example, methylenedioxy or ethylenedioxy, as well as isopropylidenedioxy groups, cycloalkoxy, for example, cyclopentyloxy, cyclohexyloxy or adamantyloxy, groups, phenyloxy groups, phenyl-lower alkoxy, for example, beuzyloxy or lor Z-phenylethoxy groups, or lower alkoxy groups substituted by monocyclic monoazacyclic, monooxacyclic or monothiacyclic groups of aromatic character, such as pyridyl-lower alkoxy, for example, 2-pyridylmethoxy groups, furyl-lower alkoxy, for example, furfuryloxy groups, or thienyl-lower alkoxy, for example, Z-thienyloxy groups.

As etherified mercapto groups, lower alkylmercapto, for example, methylmercapto or ethylmercapto groups, phenylmercapto groups, or phenyl-lower alkylmercapto, for example, benzylmercapto groups may be mentioned.

Esterified hydroxyl groups are primarily halogen, for example, fluorine, chlorine, bromine or iodine atoms, as well as lower alkanoyloxy, for example, acetyloxy or propionyloxy groups.

Substituted amino groups are monosubstituted or disubstituted amino groups, in which the substituents primarily represent optionally substituted monoor divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals, as well as acyl groups. Such amino groups are especially lower alkylamino or dilower alkylamino groups, for example, methylamino, ethylamino, dimethylamino or diethylamino groups, or lower alkyleneamino groups, which are optionally interrupted by hetero-atoms, such as oxygen or sulfur atoms or nitrogen atoms which are optionally substituted, for example, by lower alkyl groups, such as pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino groups, as well as acylamino groups, especially lower alkanoylamino groups, such as acetylamino or propionylamino groups.

Lower alkanoyl is e.g. acetyl or propionyl.

A carbo-lower alkoxy radical is, for example, a carbomethoxy, carbethoxy, carbo-n-propyloxy, carbo-isopropyloxy, carbo tert. butyloxy or carbo-tert.-pentyloxy group.

Optionally N-substituted carbamoyl groups are, for example, N-lower alkyl-carbamoyl or N,N-di-lower alkylcarbamoyl groups, such as *N-methyl-, N-ethyl-, N,N-dimethylor N,N-diethyl-carbamoyl groups.

A carbo-lower alkenyl radical is, for example, the carbovinyloxy group, While carbo-cycloalkoxy and carbophenyl-lower alkoxy groups, in Which the cycloalkyl or phenyl-lower alkyl radical have the abovementioned significance, represent, for example, carbo-adamantyloxy, carbo-benzyloxy or carbo-diphenylmethoxy, as well as carbo-(a 4 biphenylyl-u-methylethoxy) groups. Carbolower alkoxy groups in which the lower alkyl radical contains, for example, a monocyclic monoazacyclic, monooxacyclic or monothiacyclic group are, for example, carbofuryl-lower alkoxy, such as carbo-furfuryloxy groups, or carbo-thienyl-lower alkoxy, such as carbo-2-thienyloxy groups.

The new compounds show valuable pharmacological properties. Thus, they are active against micro-organisms, for example, gram-positive bacteria, such as Staphylococcus aureus, in dilutions of up to 0.01% and are therefore useful as antibacterial substances. Furthermore, they also serve as intermediates for the manufacture of valuable compounds, for example, pharmacologically active compounds.

Particularly valuable compounds are those compounds of the Formula I, wherein R and R have the abovementioned significance and R represents an optionally substituted aliphatic or aromatic hydrocarbon residue, such as one of the abovementioned corresponding residues, especially a lower alkyl, such as a methyl residue, or a monocyclic aromatic hydrocarbon, especially a phenyl residue which is optionally substituted, for example, as mentioned above. These are primarily compounds of the formula wherein R represents a lower alkyl, especially methyl residue, as Well as a phenyl residue which is optionally substituted by lower alkyl or lower alkoxy groups or halogen atoms, and Ac represents an acyl residue occuring in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or of 7-amino-cephalosporanic acid, such as, for example, the residue of the formula Y-(C H )CO, wherein m represents an integer from to 4, preferably 1, and a carbon atom of the preferably unbranched alkylene residue of the formula can optionally be substituted by an optionally substituted amino group, a free, etherified or esterified hydroxyl or mercapto group or a free or functionally modified carboxyl group, for example, by one of the abovementioned groups of this kind, and wherein Y stands for an aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, the latter preferably of aromatic character, optionally substituted in the nucleus, for example, by the substituents of the above alkylene radical, as well as by sulfo or nitro groups, or for a hydroxyl or mercapto group which is etherified by an aromatic or cycloaliphatic hydrocarbon radical or by a heterocyclic radical, the latter preferably of aromatic character, for example, a 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, Z-methoxy-naphthoyl, 2- ethoxy-naphthoyl, phenylacetyl, phenyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, uphenyloxyphenylacetyl, or. methoxy phenylacetyl, amethoxy-3,4-dichlorophenylacetyl, a cyano-phenylacetyl, phenylglycyl (optionally having a protected amino group), benzyloxycarbonyl, benzylthioacetyl, benzylthiopropionyl, hexahydrobenzyloxycarbonyl, cyclopentanoyl, u-aminocyclopentanoyl or a-amino-cyclohexanoyl (optionally having a protected amino group), 2-thienylacetyl, a-cyano- 2-thienylacetyl, a-amino-2-thienylacetyl (optionally having a protected amino group), 3-thienylacetyl, 2-furylacetyl, 2-phenyl 5 methyl-ioxazolyl-carbonyl or 2-(2- chlorophenyl) 5 methyl-isoxazolylcarbonyl group, or represents a radical of one of the formulae C H CO'- and C H- CO-, wherein n represents an integer up to 7, and the chain can be straight or branched and optionally interrupted by an oxygen or sulfur atom and/ or substituted, for example, by halogen atoms, trifiuoromethyl, free or functionally modified carboxyl, such as cyano, free or substituted amino or nitro groups, for example, a propionyl, butyryl, hexanoyl, octanoyl, butylthio-acetyl, acrylyl, crotonyl, Z-pentenoyl, allylthioacetyl, chloroacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl, 2-carboxypropionyl, cyanoacetyl or 2-cyano-3-dimethylacrylyl group, or represents a radical of the formula ZNHCO--, wherein Z denotes an aromatic or aliphatic hydrocarbon radical which is optionally substituted, especially a lower alkyl radical substituted by lower alkoxy groups and/ or halogen atoms, and primarily a monocyclic arylacetyl or aryloxyacetyl or a lower alkanoyl or alkenoyl radical, e.g. phenylacetyl, 4-hydroxy-phenylacety1, phenyloxyacetyl, hexanoyl, heptanoyl or 2-hexenoyl radical, or represents an easily removable acyl radical, especially the radical of a half-ester of carbonic acid, such as a carbolower alkoxy, for example, carbo-tert.-butyloxy or carbotert.-pentyloxy radical, a carbo-cycloalkoxy, for example, carbo-adamantyloxy radical, a carbo-phenyl-lower alkoxy, for example, carbo-diphenylmethoxy radical, or a carbofufyl-lower alkoxy, for example, carbo-furfuryloxy radica The above compounds of the Formula I, wherein R represents a formyl group, are obtained, when a 2-hydroxy 3,3 dimethyl-6-N-Ac -amin'o-4-thia-l-aza-bicyclo [3,2-0]heptan-7-one compound (configuration of fi-arninopenicillanic acid) of the formula o H- H CH Ac-NH s a (II) wherein Ac has the significance of an aryl residue Ac, in which free functional groups optionally present are protected, is treated with an oxidising agent furnishing an acyloxy group of the formula O -C(=O)R and, if desired, in a resulting compound having an acyl residue with protected functional groups, these groups are liberated, and/or, if desired, a resulting isomer mixture is resolved into the individual isomers.

In the above starting material, free functional groups in the acyl residue Ac which have to be protected during the reaction, for example in a manner which is in itself known, are primarily free hydroxyl, mercapto and amino groups, as well as carboxyl groups. The latter can, for example, be protected by conversion into an ester, for

' example, an ester which is easily split under acid conditions, such as a methyl ester which is polysubstituted by optionally susbtituted aliphatic or aromatic hydrocarbon residues, such as the tert.-butyl ester, or an ester which is easily split by reduction, such as a Z-halogeno-lower alkyl ester, especially the 2,2,2-trichloroethyl ester, and the former, for'example, by conversion into an acyl derivative, which is easily split-able under acid conditions, such as a carbo-lower alkoxy derivative, in which the lower alkyl residue in the (Z-POSltlOl'l is preferably branched or, for example, substituted by optionally substituted aromatic hydrocarbon residues, such as the carb0-tert.-butyloxy derivative, or into a carbo-Z-halogeno-lower alkoxy derivative, which is easily split by reduction, such as the carbo-2,2,2-trichloroethoxy derivative.

Oxidizing agents furnishing acyloxy groups of the formula OC-(=O)-R are preferably oxidizing heavy metal carboxylates, preferably lead-IV-carboxylates, such as lead-IV-alkylcarboxylates, especially lead-IV-lower alkylcarboxylates and primarily lead-tetracetate, also lead tetrapropionate or lead tetrastearate, as Well as optionally substituted lead tetrabenzoates, for example, lead tetrabenzoate or lead tetra-3-bromobenzoate, also thallium-III- carbox-ylates, for example, thallium-III-acetate, or mercury-II-canboxylates, such as mercury-II-acetate. If desired, these oxidizing agents can be formed in situ, for example, by reacting lead dioxide or mercury-II-oxide with an organic carboxylic acid, such as acetic acid. At least an equivalent amount of the oxidizing regent is used; normally and excess thereof is employed.

The above heavy metal carboxylates, especially the corresponding lead-IV compounds, are advantageously used in the presence of a source of light, the process preferably being carried out under ultra-violet light, as well as light of longer wavelengths, such as visible light, optionally with the addition of suitable sensitizers. Ultra-violet light has preferably a main wavelength range of above 280 m primarily of about 300 my to about 350 m this can, for example, be achieved by suitably filtering the ultra-violet light through an appropriate filter, for example, a glass filter, or through suitable solutions, such as salt solutions, or other liquids which absorb light of Shorter wavelengths, such as benzene or toluene. The ultraviolet light is preferably generated by means of a high pressure mercury vapour lamp.

The above reaction can, for example, be carried out by treating a starting material of the Formula II with the necessary quantity, usually an excess of the oxidising agent furnishing an acyloxy group of the formula --OC(=O)-R usually in the presence of a suitable diluent, such as benzene, acetonitrile or acetic acid, if necessary, while cooling or warming and/or in an inert gas atmosphere, while irradiating with ultraviolet light.

In a compound resulting from the procedure of the invention, protected functional groups in an acyl residue may be liberated in a known manner. Thus, a suitable acyl residue, such as a carbo-lower alkoxy residue which can be split under acidic conditions, for example, the carbotert.-butyloxy, as well as carbo-tert.-pentyloxy, carbo-adamantyloxy or carbo-diphenylmethoxy residue, or a carbo- 2-halogeno-lower alkoxy residue which can be split by reduction, for example, the carbo-2,2,2-tiichloroethoxy residue, can be split 01f, the latter, for example, 'by treatment with chemical reducing agents, especially with zinc in the presence of aqueous acetic acid, and the former, for example, by treatment with trifluoracetic acid.

The starting materials used in accordance with the process can be manufactured by treating a 2-isocyanato- 3,3 dimethyl 6-N-Ac -amino-4-thia-1-azal:oicyclo[3,2,0] heptan-7-one (configuration of 6-amino-penicillanic acid of the formula (III) (configuration of 6- amino-penicillanic acid) with a chemical reducing agent in the presence of water, and, if desired, resolving a resulting isomer mixture into the individual isomers.

The 2-halogeno-lower alkyl radical R may contain one, two or more halogen, i.e. chlorine, bromine or iodine atoms, with 2-chloroand Z-bromo-lower alkyl radicals containing several, preferably three chlorine and bromine atoms, respectively, whereas a 2-iodo-lower alkyl radical may have only one iodine atom. The radical R especially represents a 2-polychloro-lower alkyl, such as a 2-polychloroethyl, primarily the 2,2,2-tric'hloroethyl, as well as the 2,2,2-trichloro-l-methyl-ethyl radical, but can also, for example, denote a 2-polybromo-lower alkyl, such as 2,2,2-tribromoethyl, or a 2-iodo-lower radical, for example, the 2-iodoethyl radical.

The reaction of a compound of Formula III with a suitable 2-halogeno-lower alkanol, is optionally carried out in an inert solvent, for example, in a halogenated hydrocarbon, such as carbon tetrachloride, chloroform or methylene chloride or in an aromatic solvent, such as benzene, toluene or chlorobenzene, preferably while warming.

In this reaction it is possible to start from precursors of compounds of the Formula III, form the latter under the reaction conditions and thus to obtain the desired starting materials directly. If, for example, an appropriate 3,3-dimethyl-6-N-Ac amino 7 oXo-4-thia-1-aza-2- bicyclo[3,2,01heptane-carboxylic acid azide (configuration of 6-amino-penicillanic acid), which can, for example, be obtained by converting a 3,3-dimethyl-6-N-Ac amino-7-oxo-4-thia-1-aza-2 bicyclo[3,2,0]heptane carboxylic acid (configuration of 6-arnino-penicillanic acid), for example, a 6-N-Ac -amino-penicillanic acid, or a suitable salt, especially an ammonium salt thereof, into a mixed anhydride (for example, by treatment with a halogenoformic acid lower alkyl ester, such as chloroformic acid ethyl ester, in the presence of a basic reagent, such as triethylamine) and treating the latter with a metal azide, such as sodium azide, or an ammonium azide, for example, benzyltrimethylammonium azide, is used, this azide, in the absence or presence of the 2-halogenolower alkanol, decomposes with the evolution of nitrogen under the reaction conditions, for example, on warming, to give the desired isocyanato compound of the Formula III, which usually does not have to be isolated and which in the presence of the 2-halogeno-lower alkanol is directly converted to the desired starting material.

In a compound resulting from the above procedure the chlorine or bromine atom in a 2-monochloroand 2- monobromo-lower alkyl radical, respectively, may be ex changed for an iodine atom, for example, by treatment with a suitable iodine salt, such as an alkali metal iodide, e.g. potassium iodide, in the presence of a suitable solvent, e.g. acetone.

In an intermediate obtainable in accordance with the above process an acyl radical, especially the acyl radical of a suitable half-ester of carbonic acid, such as a carbolower alkoxy radical which can be split under acid conditions, for example, the carbo-tert.-butyloxy, as well as carbo-tert.-pentyloxy, carbo-adamantyloxy or carbodiphenylmethoxy radical, for example, by treatment with trifiuoracetic acid.

In a resulting intermediate with a free amino group the latter can be acylated according to methods which are in themselves known, for example, like a free hydroxyl group in the manner described below, i.e. by treatment with a free carboxylic acid or especially a reactive functionally modified carboxylic acid, for example, with an acid chloride or acid anhydride, optionally in the presence of a suitable condensing reagent.

The treatment of an intermediate with the chemical reducing agent is carried out under mild conditions, in most cases at room temperature or even with cooling. At least one mole, usually an excess of water is present.

Chemical reducing agents are primarily suitable reducing metals, as Well as reducing metal compounds, eg metal alloys or metal amalgams, as well as strongly reducing metal salts. Particularly useful are zinc, zinc alloys, e.g. zinc-copper or zinc amalgam, furthermore magnesium, which reagents are advantageously used in the presence of hydrogen-furnishing compounds capable of producing nascent hydrogen together with the metals, metal alloys and metal amalgams, zinc, for example, in the presence of acids, such as organic carboxylic, e.g. lower alkane carboxylic acids, above all acetic acid, with the addition of water, as well as in the presence of aqueous alcohols, such as lower alkanols, e.:g. methanol, ethanol or isopropanol, which may be used together with an organic carboxylic acid, and alkali metal amalgams, such as sodium or potassium amalgam, as well as aluminum amalgam in the presence of moist solvents, such as ethers or lower alkanols. Strongly reducing metal salts are primarily chromium-II compounds, for example, chromium-II-chloride or chromium-II-acetate, which are used in the presence of aqueous media, containing organic solvents miscible with water, such as lower alkanols, lower alkanecarboxylic acids or ethers, for example, methanol, ethanol, acetic acid, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.

The compounds of the Formula I, wherein R represents a hydrogen atom, can be obtained, when a compound of the formula or a O-ester thereof, especially an O-ester with an organic carboxylic acid, as well as a carbonic acid semideriv'ative, is treated with an oxidising agent which furnishes an acyloxy group of formula and, if desired, in a resulting compound having an acyl residue with protected functional groups these groups are liberated, and/or, if desired, a resulting isomer mixture is resolved into the individual isomers.

O-esters of compounds of Formula V are primarily those with organic carboxylic acids, such as the abovementioned optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acids, as well as with semi-derivatives of carbonic acid, also those with organic sulfonic acids, as well as with inorganic acids such as hydrohalic acids, for example, hydrogen chloride or hydrogen bromide.

Oxidising agents furnishing acyloxy groups, which are primarily used in the above process, are the above-mentioned oxidising heavy metal carboxylates, especially lead- IV-alkanoates and preferably lead tetraacetate, with the process, as mentioned, being carried out with at least an equivalent amount, usually an excess of the oxidizing reagent, and advantageously in the presence of a light source, primarily a source of ultraviolet light, and a suitable solvent or diluent.

In a resulting compound, a suitable protecting residue, such as carbo-lower alkoxy residue which can be split off under acidic conditions, for example, the carbo-tert.- butyloxy, as well as carbo-tert.-pentyloxy, carbo-adamantyloxy or carbodiphenylmethoxy residue, or a carbo- 2-halogeno-lower alkoxy residue which can be split by reduction, for example, the carbo-2,2,2-trichloroethoxy residue, can be split off, the latter, for example, by treatment with chemical reducing agents, especially with zinc in the presence of aqueous acetic acid, and the former, for example, by treatment with trifiuoracetic acid.

The starting substances of Formula V used in accordance With the process can be obtained, when a 2-hydroxy- 3,3-dimethyl-6-N-Ac -amino 4 thia-l-aza-bicyclo[3,2,0] heptan-7-one compound of Formula II is treated with a hydride reducing agent which is inert towards amide groupings, and, if desired, esterifying the hydroxyl group in a resulting compound and/or, if desired, splitting an acylamino grouping in a resulting compound, and, if desired, acylating the liberated amino group, and/or, if desired, liberating in a resulting compound having an acyl radical with protected functional groups such groups, and/or, if desired, resolving a resulting isomer mixture into the individual isomers.

Hydride reducing reagents which do not reduce an amide grouping are primarily hydrides containing boron, such as, for example, diborane and especially alkali metal or alkaline earth metal borohydrides, above all sodium borohydride. Complex organic aluminum hydrides, such as alkali metal tri-lower alkoxy-aluminum hydrides, for example, lithium-tri-tert.-butyloxy-aluminum hydride, can also be used.

These reducing agents are preferably used in the presence of suitable solvents or mixtures thereof, alkali metal borohydride, for example, in the presence of solvents possessing hydroxyl or ether groupings, such as lower alkanols, for example, methanol or ethanol, as well as isopropanol, furthermore tetrahydrofuran or diethylene- 10 glycol dimethyl ether, with cooling or warming, if necessary.

The free hydroxyl group in a compound obtainable in this way can be acylated in a manner which is in itself known. The usual acylating agents, such as acids or their reactive derivatives are used for this purpose, the former, for example, in the presence of a suitable condensation agent, such as a carbodiimide, for example, dicyclohexylcanbodiimide, and the latter, if necessary, in the presence of a basic reagent, such as an organic tertiary base, for example, triethylamine or pyridine. Reactive derivatives of acids are anhydrides, including internal anhydrides, such as ketenes, isocyanates or isothiocyanates, or mixed anhydrides, especially anhydrides which can be manufactured with halogenoformic acid esters, for example, chloroformic acid ethyl ester, and furthermore halides, primarily chlorides, or reactive esters, such as esters of acids with alcohols or phenols containing electron-attracting groupings, as well as with N-hydroxy compounds, for example, cyanomethanol, p-nitrophenol or N-hydroxysuccinimide. The acylation reaction can be performed in the presence or absence of solvents or solvent mixtures, if necessary, with cooling or warming, in a closed vessel under pressure and/or in an inert gas atmosphere, for example, nitrogen atmosphere. Esters with inorganic acids, such as hydrohalic acids, can be formed in a manner known per se, for example, by treatment with the usual halogenating agents, such as halides of sulfur and of phosphorus, for example thionyl chloride or phosphorus oxychloride.

As has been mentioned, the 1-R -2a-(2-R -carbonyloxy- 2-propylmercapto -3ot- N-Ac-amino -azetidin-4-one compounds of the above Formula I can also be used for the manufacture of pharmacologically active compounds or of compounds which can be used as intermediate products, especially of 1 R 2oz isopropenyl-mercapto 3a Acamino-aZetidin-4-one compounds of the formula CH3 (VIa) wherein Ac has the significance given above.

The compounds of the Formula VI can be obtained, when a compound of Formula I is thermally decomposed and, if desired, in a resulting compound a formyl group R is split off and/ or, if desired, in a resulting compound with an acyl residue having protected functional groups, these groups are liberated and/or, if desired, a resulting isomer mixture is resolved into the individual isomers.

The thermal decomposition of the starting material is preferably performed in the presence of an inert solvent or solvent mixture, especially a suitable hydrocarbon, such as an aliphatic or aromatic hydrocarbon, for example, high-boiling petroleum ether, benzene, toluene or xylene, at temperatures of about 50 C. to about 150 C., preferably from about 70 C. to about C., and, if desired, in an inert gas, such as a nitrogen atmosphere.

In a resulting compound of Formula VI, in which R represents the formyl radical, the latter can be replaced by hydrogen by hydrolysis, alcoholysis, ammonolysis or aminolysis, as well as by treatment with a specific decarbonylation reagent. Hydrolysis can, for example, be performed in an aqueous medium by treatment with a suitable inorganic base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example, sodium potassium, calcium or barium hydroxide or carbonate, as well as an alkali metal hydrogen carbonate, for example, sodium or potassium hydrogen carbonate. The alcoholysis with alcohols, such as lower alkanols, for example, methanol or ethanol, as well as with mercaptans, is preferably carried out in the presence of appropriate alcoholates or thiolates, such as alkali metal lower alkanolates, for example, sodium methylate or ethylate, as well as of weakly basic acylates, such as alkali metal lower alkanoates, for example, sodium acetate.

The ammonolysis with ammonia, as well as with quaternary ammonium hydroxides, for example, benzyltrimethylammom'um hydroxide or tetrabutylammonium hydroxide, also leads to the removal of a formyl group R When using ammonia the process is, for example, carriedbut in a two-phase system; the ammonia, which is preferably used in the form of an aqueous solution, passes then into the organic phase at a low concentration and effects the splitting-01f of the formyl group. Aminolysis can be carried out with amines, especially primary or secondary, pri marily aliphatic or aromatic, amines, for example, ethylamine, diethylamine, pyrrolidine or aniline.

Specific decarbonylation reagents are, for example, complex transition metal compounds which can form a stable complex together with carbon monoxide, such as tri-substituted ,tris-phosphine-rhodiurn halides, for example, tris-(triphenyl)-phosphine-rhodium chloride. They are preferably used in a suitable inert solvent, for example, benzene or a solvent mixture, if desired, in an inert gas, for example, nitrogen atmosphere.

The removal of the formyl group, which, for example, when using a decarbonylating agent, is preferably carried out at elevated temperature, can also be directly performed on a compound of the Formula I, in which R represents a formyl group; under these conditions the thermal decomposition occurs with formation of the isopropenyl residue and the formyl group is simultaneously replaced by hydrogen.

Compounds which can be manufactured using compounds of Formula VI as starting materials are, for example, those of the formula CH; R-Nfr "s-o OH; (VII) especially of the formula O C-NR.,

H- H CH3 '-N'1 :t "s-o oH, (VIIa) wherein R represents a hydrogen atom or the acyl radical Ac of an organic carboxylic acid, especially of one of the abovementioned optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acids, as well as the acyl radical of a carbonic acid semi-derivative, and R, represents a hydrogen atom or the acyl radical Ac of a lower alkanecarboxylic acid, including formic acid.

Compounds of the above nature, especially those, in which R and R or R and R, represent acyl groups, show valuable pharmacological properties; in particular, they are active against gram-positive bacteria, such as Staphylococcus aureus in dilutions ranging to 0.01% and are, therefore, useful accordingly. They can also serve as intermediate products, such as for the manufacture of valuable compounds, for example, pharmacologically active compounds.

They can be obtained, when the isopropenyl group is saturated in compounds of Formula VI and, if desired, in a resulting compound the formyl group is split off and/ or, if desired, in a resulting compound the nitrogen atom of the lactam grouping carrying the hydrogen atom is acylated and/or, if desired, in resulting compound an acylamino grouping is split and, if desired, the liberated amino group is acylated and/or, if desired, in a resulting compound having an acyl radical with protected functional groups these groups are liberated and/or, if desired, a resulting isomer mixture is resolved into the individual isomers.

The reduction of the isopropenyl radical in the starting material of Formula VI is preferably performed by treatment with catalytically activated hydrogen, for example, with hydrogen in the presence of a noble metal catalyst which, for example, contains palladium or platinum, if necessary, at elevated pressure and/or with heating.

A formyl group R can be replaced by hydrogen and the latter by an acyl group, for example, according to the decarbonylation and acylation methods described above, the latter preferably at an elevated temperature, while in a resulting compound it is possible, if desired, to split a suitable acylamino grouping in the manner mentioned above, and if desired, to acylate a free amino group formed in this way; protected functional groups can be liberated, for example, as mentioned above.

Compounds of Formula VI, primarily those in which Ac represents an acyl radical Ac which is easily removable, especially under acid conditions, such as a suitable acyl radical of a carbonic acid half-ester, such as a carbolower alkoxy radical, which is optionally substituted in the lower alkyl portion, preferably in the tat-position, as well as a carbo-lower alkenyloxy, carbo-cycloalkoxy, carbo-phenyloxy or carbo-phenyl-lower alkoxy radical which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl and phenyl-lower alkyl portion, respectively, or a carbo-lower alkoxy radical having a heterocyclic group of aromatic character in the lower alkyl portion, preferably in the d-POSitiOIl, and R denotes a hydrogen atom, can furthermore be converted to compounds of the formula HaC \CHa (VIII) especially to those compounds, in which R has the significance of R; compounds of this type are known, for example, as valuable intermediate products in the synthetic manufacture of 7-acylamino-cephalosporanic acid compounds; see, for example, Austrian Pats. Nos. 263,768 and 264,537.

They are obtained, when compounds of Formula VI, wherein Ac preferably represents one of the abovementioned easily removable radicals Ac, are treated with a strong oxygen-containing acid, and, if desired, in a resulting compound of Formula VIII having an unsubstituted nitrogen atom in the 3-position, the latter is acylated.

The ring closure can be effected by treatment with a strong inorganic or organic oxygen-containing acid, such as organic carboxylic or sulfonic acids, especially a strong lower alkanecarboxylic acid, which is optionally substituted by hetero-radicals, preferably by halogen atoms, such as an u-halogeno-acetic or a-halogenopropionic acid, wherein halogen preferably denotes fluorine, as well as chlorine, primarily trifluoroacetic acid. The reaction is 13 carried out in the absence or presence of an inert solvent, such as dioxane, or of a mixture of diluents and, if necessary, with cooling, for example, at temperatures of about -30 to about +10 C., and/or in an inert gas, for example, nitrogen atmosphere.

Acylation of a hydrogen-containing nitrogen atom in a resulting compound can, for example, be carried out as described above, if desired, in stages.

Mixtures of isomers obtainable according to the above processes can be resolved into the individual isomers according to methods which are in themselves known, for example, by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other I suitable resolution processes. Resulting racemates having salt-forming groups, into which, in view of the racemate resolution, suitable substituents can temporarily be introduced in the usual manner, can be resolved into the antipodes in the usual manner, for example, by forming a mixture of diastereo-isomeric salts with optically active salt-forming reagents, resolving the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds, or by fractional crystallization from optically active solvents.

The above processes also comprise those modifications according to which compounds formed as intermediates are used as starting materials and the remaining process stages are carried out with these or the process is interrupted at any stage; furthermore, starting materials can be used in the form of derivatives, for example, of salts, or can be formed during the reaction.

The invention also comprises new intermediate products, as well as processes for their manufacture.

Preferably, those starting materials are used and the reaction conditions are so chosen that the compounds mentioned above as being preferred are obtained.

The compounds of the present invention having pharmacological efiect can, for example, be used in the form of pharmaceutical preparations in which they are in admixture with a solid or liquid pharmaceutical excipient and which are suitable for enteral or parenteral administration. Suitable excipients, which are inert towards the active substances, are, for example, water, gelatine, saccharides, such as lactose, glucose or sucrose, starches, such as corn starch, wheat starch or arrowroot, stearic acid or salts thereof, such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known excipients. The preparations may be in solid form, for example, as tablets, dragees, capsules or suppositories, or in a liquid form, for example, as solutions, suspensions or emulsions. They can be sterilized and/ or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and/ or buffers. They can, furthermore, contain other pharmacologically usable substances. The pharmaceutical preparations, which are also comprised by the present invention, can be formulated in a manner which is in itself known.

The invention is described in the following examples;-

temperatures are given in degrees centigrade,

EXAMPLE 1 A solution of 0.065 g. of 2-hydroxy-3,S-dimethyl-fi- (N-phenyloxyacetyl-amino)-4-thia l azabicyclo[3.2.0.] heptan-7-one (configuration of -6-amino-penicillanic acid) in ml. of benzene is treated with 0.15 g. of lead tetraacetate containing 10% of acetic acid, and the yellow solution is irradiated by means of a high pressure mercury vapour lamp (80 watts) in a water-cooled Pyrex glass jacket. After 10 minutes the yellow color disappears and a partially flocculent and white, partially gum-like and yellow precipitate forms. The mixture is diluted with benzene, washed with water, a dilute aqueous sodium hydrogen carbonate solution and water, and evaporated under reduced pressure. The 1-formyl-2a-(Z-acetyloxy-Z- 14 propyl-mercapto) 3a (N-phenyloxyacetyl-amino)-azetidin-4-one of the formula is thus obtained as a slightly yellowish gum-like product; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.05 556p, 5.78 5.90 627 6.62p., 6.71,u, 7.33p., 7.67m 8.92;, 9.24 and 9.8244.

EXAMPLE 2 A solution of 0.1 g. of 2-hydroxy-3,3-dimethyl-6-(N- phenylacetyl amino) -4-thia-1-azabicycl0 [3.2.0]heptan-7- one (configuration of G-amino-penicillanic acid) in 10 ml. of benzene is treated with 0.24 g. of lead tetraacetate containing 10% of acetic acid, and the yellow mixture is irradiated, while stirring at 10", by means of a high pressure mercury vapour lamp watts) in a water-cooled Pyrex glass jacket. After 20 minutes no further tetravalent lead compound can be detected and the reaction mixture is colorless, with a yellowish precipitate having settled on the walls of the vessel. The mixture is diluted with benzene, washed with water and a dilute aqueous sodium hydrogen carbonate solution and evaporated under reduced pressure at a temperature below 25*30. The amorphous l-formyl-2w(Z-acetyloxy- 2-propyl-mercapto -3 oz- (N- phenylacetyl-amino -azeti'din- 4-one of the formula O=CN--CHO err-on CH: @om-c-Nir "s --o o--c1;r

(l H, l)

is thus obtained; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.04 5.56 5.78;/., 5.87 6:69p, 7.33 7.68/L, 8.57,u., 8.93 and 9.84

EXAMPLE 3 A solution of 0.3 g. of 2-hydroxy-3,3-dimethyl-6-(N- carbo-tert. butyloxy amino)-4-thia-l-azabicyclo[3.2.0] heptan-7-one (configuration of 6-amino-penicillanic acid) in m1. of anhydrous benzene is mixed with l g. of vacuum-dried lead tetraacetate and 0.09 ml. of pyridine and the mixture is irradiated at about 12-15 with a high pressure mercury vapour lamp (Hanau; type Q 81; 80 watts) in a water-cooled Pyrex glass jacket, while keeping it agitated by passing a stream of oxygen-free nitrogen through it. A white precipitate of lead diacetate forms; a small quantity of a gum-like-black product which very probably contains metallic lead deposits on the Pyrex glass jacket and is scraped off from time to time. After 1 hour the entire quantity of lead tetraacetate has been consumed; the mixture is filtered and the filtrate is washed with a dilute aqueous sodium hydrogen carbonate solution and with water, dried and evaporated under reduced pressure. The crude l-formyl-2a-(2-acetyloxy-2-propylmercapto) 3oz (N-carbo-tert.-butyloxy-amino)-azetidin- 4-one of the formula is obtained as an amorphous product and is further processed without purification; infra-red absorption spectrum (in methylene chloride); characteristic bands at 304g, 5.56 5.88 6.70;, 7.33 1. and 8.70

EXAMPLE 4 A solution of 0.5 g. of the hydrate of 2-hydroxy-3,3- dimethyl-6-(N phenyloxyacetyl amino)-4-thia-l-azabicyclo[3.2.0]heptan-7-one (configuration of 6-amino-penicillanic acid) in 125 ml. of anhydrous benzene is treated with 1.15 g. of lead tetraacetate (containing 10% of acetic acid) and the mixture is irradiated at about 15 with a high pressure mercury vapour lamp (80 watts) in a water-cooled Pyrex glass jacket, with a slow stream of oxygen-free nitrogen being passed through. After 1% hours the originally yellow solution becomes colorless; the reaction on potassium iodide-starch paper is negative. The reaction mixture is filtered and the filtrate is diluted with benzene and washed with water, a dilute aqueous sodium hydrogen carbonate solution and water, dried and evaporated under reduced pressure. The residue contains the l-formyl-lu-(2-acetyloxy-2-propyl mercapto) -3 a- (N-phenyloxyacetyl-amino -azetidin-4-one which is further processed Without purification.

EXAMPLE 5 A solution of 1 g. of the hydrate of 2-hydroxy-3,3- dimethyl 6 (N-phenyloxyacetyl-amino)-4-thia-1-azabicyclo[3.2.0]heptan-7-one (configuration of 6-aminopenicillanic acid) in 125 ml. of anhydrous benzene is treated with 0.3 ml. of pyridine and 2.6 g. of lead tetraacetate which has been dried under reduced pressure; the mixture is irradiated at about 15 with a high pressure mercury vapour lamp (80 watts) in a water-cooled Pyrex glass jacket, with a slow stream of nitrogen (pyrogallolwashed) being passed through. After 3 hours the test on potassium iodide-starch paper is only slightly positive. The mixture is filtered, washed with 100 ml. of a dilute aqueous sodium hydrogen carbonate solution and 100 ml. of water, dried and evaporated under reduced pressure; the crude product contains the l-formyl-2a-(2-acetyloxy- 2 propylmercapto) 3a (N-phenyloxyacetyl-amino)- azetidin-4-one, which is further processed without purification.

EXAMPLE 6' A solution of 0.5 g. of the hydrate of 2-hydroxy-3,3- dimethyl 6 (N-phenyloxyacetyl-amino)-4-thia-l-azabicyclo[3.2.0]heptan 7 one (configuration of 6-aminopenicillanic acid) and 2.1 g. of lead tetrabenzoate in 160 ml. of anhydrous benzene, through which a stream of oxygen-free nitrogen is passed, is irradiated with a high pressure mercury vapour lamp (Hanau Q 81; 70 watts) at 15 in a water-cooled Pyrex glass jacket. The originally dark yellow solution becomes colorless after about 1 /2 hours; only a small quantity of a fiocculent precipitate forms which is filtered off. The filtrate is washed with water, a dilute aqueous sodium hydrogen carbonate solution and again with water, dried and evaporated under reduced pressure. The residue containing the 1-fo-rmyl-2w' (2 benzoyloxy 2 propyl-mercapto)-3 x-(N-phenyloxyacetyl-amino)-azetidin-4-one of the formula is further processed without purification.

EXAMPLE 7 A suspension of 0.08 g. of 2a-(2-hydroxymethyl-2-propyl mercapto) 3a (N phenyloxyacetyl amino)- azetidin 4 one in 25 ml. of anhydrous benzene is treated with 0.3 g. of lead tetraacetate containing 10% of acetic acid and irradiated at about 10 with a high pressure mercury vapour lamp 80 Watts) ina watercooled Pyrex glass jacket, while stirring. After 45 minutes, no further tetravalent lead compound can be detected with potassium iodide-starch paper. The precipitate forming on the walls of the vessel during the reaction is scraped off from time to time. 1 g. of polystyrene-Hiinig base (manufactured by warming a mixture of 100g. of chloro- 16 methyl-polystyrene [1. Am. Chem. Soc. 85, 2149 (1963)], 500 ml. of benzene, 200 ml. of methanol and 100 ml. of diisopropylamine to 150 while shaking, filtering, washing with 1000 ml. of methanol, 1000 m1. of a 3: 1- mixture of dioxane and triethylamine, 1000 ml. of methanol, 1000 m1. of dioxane and 1000 ml. of methanol, and drying for 16 hours at 100/100 mm. Hg; the product neutralizes 1.55 milliequivalents of hydrochloric acid per 1 g. in a 2:1-mixture of dioxane and water) is added to the mixture, which is stirred for 5 minutes and filtered, and the filtrate is evaporated at about 30- 40 under reduced pressure. The residue contains the 2a- (2 propylmercapto) 3a (Nphenyloxyacety1-amino)- azetidin-4-one of the formula which is processed without additional purification.

The 20: (2 hydroxymethyl 2 propylmercapto) 300- (N carbo tert. butyloxy amino) azetidin 4-one can be converted to the 2a (2 acetyloxy 2 propylmercapto) 3a (N carbo tert.-butyloxy-amino)- azetidin 4 one in a similar manner by treatment with lead tetraacetate.

The starting materials used in the above Examples may be prepared as follows:

EXAMPLE 8 A solution of 2.625 g. of penicillin-V in 30 m1. of tetrahydrofuran is mixed with 5.31 ml. of a 10 ml.- solution of 2 ml. of triethylamine in tetrahydrofuran while stirring and cooling to -10. 3.6 ml. of a 10 ml.- solution of 2 m1. of chloroformic acid et yl ester in tetrahydrofuran are then added slowly at '10 and after completion of the addition, the mixture is stirred for minutes at 10 to 5.

The reaction mixture is treated with a solution of 0.51 g. of sodium azide in 5.1 ml. of water, stirred for 30 minutes at 0 to -5 and diluted with 150 ml. of ice water. It is extracted three times with methylene chloride; the organic extracts are washed with water, dried and evaporated at 25 and under reduced pressure. The amorphous penicillin-V azide is thus obtained as a slightly yellowish oil; infi'ared absorption spectrum (in methylene chloride): characteristic bands at 3.04;1., 4.70 5.61 5.8244. (shoulder), 5.93,u 6,26% 6.61 1, 6.71pm, 8.50 and 9.40

A solution of 2.468 g. of penicillin-V azide in 30 ml. of benzene is heated to 70 for 30 minutes. The pure 2- isocyanato 3,3 dimethyl 6 -(N phenyloxyacetylamino) 4 thia 1 azabicyclo[3.2.0]heptan 7 one (configuration of G-amino-penicillanic acid) can be obtained by evaporating the solution under reduced pressure; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.03 4.46 5.59 5.93 6.26 1. 6.62 6.70,u, 7.53;, 8.28,u, 8.53 9.24;/. and 9.4011,.

The above solution of the 2-isocyanato-3,3-dimethyl- 6 '(N phenyloxyacetyl-amino) 4 thia 1 azabicyclo [3.2.0]heptan-7-one is mixed with 3.4 ml. of a 10 ml.- solution of 2 ml. of 2,2,2-trichloroethanol in benzene and the reaction mixture is kept for minutes at 70. The solvent is removed under reduced pressure and the residue is purified on 40 ml. of acid-washed silica gel (column). Using 300 ml. of benzene and 300 ml. of a 9: l-mixture of benzene and ethyl acetate, byproducts are washed out and the pure 2 (N- carbo 2,2,2-trichloroethoxy-amino)- 3,3 dimethyl -6 (N phenyloxyacetyl-amino) 4- H in OH.

QQ-CHZ-C-Nii is eluted with 960 ml. of a 9:1-mixture of benzene and ethyl acetate. After recrystallization from a mixture of ether and pentane, the product melts at 169-171 (decomposition); [a] =+83 (c.=1.015 in chloroform); thin layer chromatogram (silica gel): Rf=0.5 in a 1.1- mixture of benzene and ethyl acetate; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.05;, 5.62;, 5.77;, 5.93;, 6.27;, 6.62;, 6.70;, 8.30;, 9.23; and 9.50;.

Instead of the abovementioned 2 (N carbo 2,2,2- trichloroethoxy amino) 3,3 dimethyl 6 (N-phenyloxyacetyl amino) 4 thia 1-azabicyclo[3.2.0=]heptan- 7-one it is also possible to use as an intermediate, the corresponding 2 (N carbo 2,2 dichloroethoxy amino)- 3,3 dimethyl 6 (N phenyloxyacetyl amino) 4- thia 1 azabicyclo[3.2.0]heptan 7 one (configuration of 6-amino-penicillanic acid) of the formula NH-COOCHQCHClt which after recrystallization from methylene chloride and ether melts at 145-147; [a] =+89il (c.=0.963 in chloroform); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.03;, 5.60;, 5.78;, 5.93,, 6.27;, 6.60;, 6.72;, 8.28; and 9.51;.

EXAMPLE 9 15 ml. of a sulfonic acid type of ion exchanger (HQ-form) are converted to the triethylammonium salt form by treatment with a solution of 5 ml. of triethylamine in 100 ml. of water, the column is washed with 300 m1. of water until neutral and treated with a solution of 2 g. of the sodium salt of penicillin-G in .10 ml. of water, and thereafter eluted with water. A total of 45 ml. is taken and the solution is lyophilized at a pressure of 0.01 mm. Hg. The crude triethylammonium salt of penicillin-G thus obtained is dissolved in methylene chloride and the solution is dried over sodium sulfate, filtered and evaporated.

A solution of the penicillin-G triethylammonium salt obtainable in this manner, in a mixture of 40 ml. of methylene chloride and 40 ml. of tetrahydrofuran, is cooled to -10 and slowly mixed with 2.9 ml. of a 10 ml.-solution of 2 ml. of chloroformic acid ethyl ester in tetrahydrofuran while stirring. The mixture is stirred for 90 minutes at 5 to 0, then mixed with a solution of 0.395 g. of sodium azide in 4 ml. of water, and the mixture is stirred for 30 minutes at -5 to 0. It is diluted with 100 ml. of ice Water and extracted three times with 75 m1. of methylene chloride at a time; the organic extracts are washed with water, dried and evaporated at room temperature under reduced pressure. The amorphous penicillin-G azide is thus obtained, infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.05;, 4.71;, 5.62;, 5.80;, 5.94;, 6.69;. and 8.50;.

A solution of 1.72 g. of the penicillin-G azide in 30 ml. of benzene is mixed with 1.5 ml. of 2,2,2-tn'chloroethanol and stirred for 25 hours at 70. During the first 15 minutes a continuous evolution of nitrogen is observed and after a few hours the product separates out from the solution. The mixture is diluted with 60 ml. of hexane while stirring, cooled, and filtered after 15 minutes. The filter residue is washed with a 2: l-mixture of benzene and hexane and with cold ether. The pure Z-(N-carbo- 2,2,2 trichloroethoxy-amino) 3,3 dimethyl 6 (N- phenylacetyl-amino) 4 thia 1 azabicyclo[3.2.0] heptan-7-one (configuration of 6-amino-penicillanic acid) of the formula NET-CO O CHQC 01 M.P. 223223.5, is thus obtained; [u] =+172 (c.=1.018 in ethanol); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.04;, 5.61;, 5.77;, 6.57;, 6.70;t, 8.30;, 9.17;, 9.62;. and 11.85;.

The product can also be obtained by warming 0.03 g. of penicillin-G azide in 2 ml. of benzene to 70 for 20 minutes, and forming the 2-isocyanato-3,3-dimethyl-6- (N-phenylacetyl-amino) 4 thia 1 azabicyclo[3.2.0] heptan-7 one (configuration of 6 amino-penicillanic acid) by evaporating the reaction mixture under reduced pressure; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.06;, 4.48;, 5.62;, 5.96; and 6.70;; and converting this, in accordance with the process indicated in Example 8, by reaction with 2,2,2-trichloroethanol into the desired 2 (N-carbo-2,2,2- trichloroethoxy-amino) 3,3 dimethyl 6-(N-pl1enyl acetyl-amino) 4 thia 1 azabicyclo[3.2.0]heptan- 7-one (configuration of 6-amino-pem'cillanic acid).

EXAMPLE 10 A suspension of 0.5 g. of crude 6-amino-penicillanic acid in 4 ml. of chloroform (freshly distilled over phosphorus pentoxide) is treated with 1 ml. of hexamethyldisilazane of the formula [(CH Si] NI-I and 1 ml. of chloroform (dried over phosphorus pentoxide); the reaction mixture is boiled under reflux for 2 /2 hours with exclusion of atmospheric moisture, is then cooled to 0, and, atfer the addition of 1.7 ml. of a 10 ml.-solution of 2 ml. of triethylamine in chloroform, is treated with 0.385 g. of distilled fiuoroformic acid tert.-butyl ester. The mixture is kept for 30 minutes at 0 and then for minutes at room temperature and is diluted with cold methylene chloride. The organic solution is washed with a cold 10% aqueous citric acid solution and water, with the aqueous Wash solutions being back-Washed with cold methylene chloride. The combined organic extracts are twice extracted with a dilute aqueous sodium hydrogen carbonate solution and, immediately after separation, are acidified with citric acid in the presence of methylene chloride and at 0. The organic phase is separated, dried and evaporated; the pure amorphous 6 (N-carbo-tert.- butyloxy-amino)-penicillanic acid is thus obtained; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.04;, 5.63;1., 5.82;, 6.67;, 7.32; and 8.60;.; and is immediately used without purification.

The resulting 6 (N-carbo-tert.-butyloxy-amino)-penicillanic acid is dissolved in 10 ml. of methylene chloride and treated with 0.43 ml. of a 10 ml.-solution of 2 ml. of triethylamine in methylene chloride. On evaporation the 6 (N-carbo-tert.-butyloxy-amino)penicillanic acid triethylammonium salt is obtained as an amorphous residue; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.0 5;, 5.67;, 5.85;, 6.17;, 6.67;, 7.32; and 8.53;.

A solution of 0.226 g. of the 6-(N-carbo-tert.-butyloxy-amino)-penicillanic acid triethylammonium salt in 5 ml. of tetrahydrofuran is mixed at 10 with 0.26 ml. of a 10 ml.-solution of 2 ml. of chloroformic acid ethyl ester in tetrahydrofuran. After stirring for 90 minutes at 5 to 10, the mixture is treated with a solution of 0.04 g. of sodium azide in 0.4 ml. of water. The mixture is stirred for a further 30 minutes at 5 to and is then diluted with 20 ml. of ice-water and extracted with methylene chloride. The organic extract is dried and evaporated under reduced pressure at a temperature below 25 the crude 6-(N-carbo-tert.-butyl-oxy-amino)-penicillanic acid azide is obtained as the residue; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.03;, 4.70;, 5.62;, 5.83;, 6.16;, 7.32;, 8.60;! and 9.40;.

The crude product obtained above is dissolved in ml. of benzene, stirred for 5 minutes at 70, and a small amount of the solvent is evaporated; according to the infra-red spectrum (in methylene chloride: characteristic bands at 3.03;, 4.48;, 5.61;, 5.83;, 6.67;, 7.31;, 7.55; and 8.62;), the rearrangement to give the 2-isocyanato-3,3-dimethyl-6-(N carbo-tert.-butyloxy-amino)- 4-thia-1-azabicyclo[3.2.0]heptan-7-one (configuration of 6-amino-penicillanic acid) is complete. The warm benzene solution is mixed with 0.2 m1. of 2,2,2-trichloroethanol; the reaction mixture is stirred for a further 90 minutes at 70 and is then evaporated under reduced pressure. The 2-(N-carbo-2,2,2-trichloroethoxy-amino)- 3,3-dimethyl 6 (N-carbo-tert.-butyloxy-amino)-4-thial-azabicyclo[3.2.0]heptan-7-one (configuration of 6-amino-penicillanic acid) of the formula NH-C O O CHZC C1 is thus obtained as a crystalline product which after recrystallization from a mixture of ether and pentane melts at l65l67; infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.04;, 5.63;, 5.81;, 5.84;, 6.69% 7.34;, 8.65;, 9.16; and 9.591;.

EXAMPLE 1 1 A solution of 3 g. of crystalline 2-(N-carbo-2,2,2-trichloroethoxy-amino) 3,3 dimethyl 6 (N-phenyloxyacetylamino)-4-thia-1-azabicyclo[3.2.0] heptan 7 one in 65 ml. of 90% aqueous acetic acid and 30 ml. of dimethylformarnide is mixed with 32.6 g. of zinc dust over the course of 20 minutes while cooling with ice, and is stirred for 20 minutes. The excess zinc is filtered oil and the filter residue is washed with benzene; the filtrate is diluted with 450 ml. of benzene, washed with a saturated aqueous sodium chloride solution and with water, dried and evaporated under reduced pressure. The residue is purified on a column of 45 g. of acid-washed silica gel. Elution is carried out with 100 ml. of benzene and 400 ml. of a 9:1-mixture of benzene and ethyl acetate and apolar products are obtained. Starting material is eluted with 100 ml. of a 4:1-mixture of benzene and ethyl acetate, and with a further 500 ml. of the 4:1-mixture of benzene and ethyl acetate and with 200 ml. of a 2:1-mixture of benzene and ethyl acetate 2-hydroxy-3,3-dimethyl- 6 (N-phenyloxyacetyl-amino)-4-thia-1-azabicyclo[3.2.0]

20 heptan-7-one (configuration of 6-amino-penicillanic acid) of the formula is obtained; this crystallizes spontaneously as the hydrate and after trituration with ether, saturated with water, melts in an unsharp manner in the range of 62-85".

It chromatographed but non-crystalline starting material is used and the reduction is carried out in dilute acetic acid without the addition of dimethylformamide, the pure product, M.P. 6270, is obtained; thin layer chromatogram (silica gel): Rf=0.35 in a 1:1-mixture of benzene and ethyl acetate; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.93;, 3.09;, 5.65;, 5.96;, 6.29;, 6.65;, 6.75;, 8.57;, 9.27;, 10.00; and 11.95 L.

EXAMPLE 12 A solution of 2.49 g. of 2-(N-carbo-2,2,2-trichloroethoxy-amino)-3,3dimethyl-6-(N phenylacetyl-amino)- 4-thia-1-azabicyclo[3.2.0]heptan-7-one in 50 ml. of dimethylformamide, 25 ml. of acetic acid and 5 ml. of water is prepared at room temperature, and is then cooled to 0 and mixed with a total of 25 g. of zinc dust over the course of 10 minutes while stirring. The mixture is left for 20 minutes at 0, and is then filtered into a receiver containing 500 ml. of a saturated aqueous sodium chloride solution, and the filter residue is Washed with 25 ml. of acetic acid. The filtrate is extracted three times with 300 ml. of benzene at a time; the organic extracts are washed with Water, a dilute aqueous sodium hydrogen carbonate solution and water, combined, dried and evaporated under reduced pressure. The residue is chromatographed on 45 g. of acid-washed silica gel. Fractions of ml. each are taken, elution being carried out with 300 ml. of benzene, 300 ml. of a 9:1-, 500 ml. of a 4:1-, 600 ml. of a 2:1- and 200ml. of a 1:1-mixture of benzene and ethyl acetate and 100 ml. of ethyl acetate. Fractions 8 and 9 contain crystalline starting material, While the 2 hydroxy 3,3 dimethyl-6-(N-phenylacetyl-amino)-4- thia-l-azabicyclo[3.2.0]heptan-7-one (configuration of 6-amino-penicillanic acid) of the formula is obtained as a colorless oil from fractions 11-15; infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90;, 3.05;, 5.64;, 5.99;, 6.70; and 9.28;.

EXAMPLE 13 A solution of 0.5 g. of 2 (N-carbo-2,2,2-trichloroethoxy-amino) 3,3 dimethyl-6-(N-carbo-tert.-butyloxyamino) 4-thia-1-azabicyclo[3.2.0]heptan-7-one (configuration of 6-arnino-penicillanic acid) in 5 ml. of tert.- butanol is diluted with 4 ml. of acetic acid and 1 ml. of water. After cooling in an ice bath, 5 g. of zinc dust are added in small portions over the course of 15 minutes while stirring. The mixture is stirred for a further 30 minutes at 0 and is then filtered into a receiver containing 70 ml. of a saturated aqueous sodium chloride solution. The residue is washed with methylene QhlQIide and the aqueous phase of the filtrate is extracted with the same solvent. The organic extracts are washed with a saturated sodium chloride solution, dried and evaporated under reduced pressure. The crude product thus obtained can be purified by chromatography on 10 g. of acid-washed silica gel, a forerun being taken with a 9: l-mixture of benzene and ethyl acetate, and the 2-hydroxy-3,3-dimethyl-6-(N- carbo-tert.-butyloxy-amino) 4- thia -1-azabicyclo[3.2.0] heptan-7-one(configuration of 6-amino-penicillanic acid) of the formula being then eluted as a colorless oil with the same solvent mixture and with a 4: l-mixture of benzene and ethyl acetate. This material crystallizes from a mixture of ether and pentane, M.P. 106110 (sintering from 100 up); [at] =l15:l (c.=0.858 in chloroform); thin layer chromatogram (silica gel); Rf-0.53 in a 1:1-mixture of benzene and ethyl acetate; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.91 3.04 5.64,tt, 5.84 6.68 t, 734 and 8.60

EXAMPLE 14 A solution of 0.18 g. of 2-hydroxy-3,3-dimethyl-6-(N- phenyloxyacetyl-amino) 4 thial-azabicyclo[3.2.0]heptan-7-one hydrate (configuration of 6-amino-penicillanic acid) in ml. of tetrahydrofuran is mixed at 0 with 0.3 ml. of a solution of 0.38 g. of sodium borohydride in 5 ml. of water. The mixture is stirred for 20 minutes at 0, then adjusted to pH-4 by adding 12 drops of acetic acid and is diluted with 50 ml. of methylene chloride. The organic solution is twice washed with a saturated aqueous sodium chloride solution, the aqueous solutions are backwashed with methylene chloride and the combined organic solutions are dried and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of methylene chloride and ether, whereupon the 2m (Z-hydroxymethyl-2-propyl-mercapto)-3 ot-(N-phenyloxyacetylamino)-azetidin-4-one of the formula O=CNH CHC H 0H3 Quota-corn "s-c i-omon g (ilHz is obtained as a slightly yellowish, oily product which can 22 be purified by chromatography on acid-washed silica gel and elution with a 9: l-mixture of benzene and ethyl acetate. The amorphous product shows the following characteristic bands in the infra-red absorption spectrum (in methylene chloride): 3.05 556p, 5.88 r, 6.28,u, 6.72 and 7.68/L.

Example 16 A mixture of 0.075 g. of 1-formyl-2u-(2-acetyloxy-2- pro pyl-mercapto 3 a- (N-phenylacetyl-amino -azetidin-4- one and 7.5 ml. of anhydrous benzene is boiled for 6 /2 hours under reflux and then evaporated under reduced pressure. The amorphous 1 formyl2a-isopropenyl-mercapto 30: (N-phenylacetylamino)-azetidin-4-one of the formula l l err-on 0Hi Gerri-Earn so \CH3 thus obtained shows characteristic bands at 305 5.56 5.90 6.70 and 7.70/1. in the infra-red absorption spectrum (in methylene chloride).

EXAMPLE 17 The crude product resulting from the process of Example 3, containing the 1 formyl 2a-(2-acetyloxy-2- propyl-mercapto) 3oz (N-carbo-tert.-butyloxy-amino)- azetidin-4-one, is dissolved in 15 ml. of toluene and heated for 17 hours in a nitrogen atmosphere at The mixture is evaporated under reduced pressure and the crude 1-formyl-2a-isopropenylmercapto-3a-(N-carbo-tert.butyloxy-amino)-azetidin-4-one of the formula is obtained as an amorphous product which shows the following characteristic bands in the infra-red spectrum (in methylene chloride): 3.03 5.55 5.85,u., 6.69,u and 732 EXAMPLE 18 The crude l formyl 2a-(2-acetyloxy-Z-propyl-mercapto)-3a-(N-phenyloxyacetyl-amino)-azetidin-4 one resulting from the process of Example 5 is dissolved in 50 ml. of toluene and kept for 16 hours at 90 under a nitrogen atmosphere and then evaporated under reduced pressure. The residue contains the 1-formyl-2u-isopropenylmercapto-3 ot-(N-phenyloxyacetylamino) azetidin 4 one which is further processed without purification.

EXAMPLE 20 A solution of 0.741 g. of the residue resulting from the process of Example 6, containing 1-formyl-2a-(2-benzoyloxy-2-propylmercapto) -3 a-(N phenyloxyacetyl amino)- azetidin-4-one, in 25 ml. of toluene is heated for 16 hours at 90 and is then cooled and diluted with benzene. The organic solution is washed with a dilute aqueous sodium hydrogen carbonate solution and water, dried and evaporated under reduced pressure. The 1-formyl-2u-isopropenylmercapto-3a-(N-phenyloxyacetyl-amino) azetidin- 4-one obtained as a residue is further processed without purification.

EXAMPLE 21 A solution of 0.051 g. of 1-formyl-2a-(2-acetyloxy-2- propyl-mercapto)-3a-(N-phenyloxyacetyl-amino) azetidin-4-one in 2 ml. of anhydrous benzene is treated with 0.13 g. of tris-triphenyl-phosphine-rhodium chloride and boiled for 3 hours under reflux. The initially red solution changes color to brown, with a small quantity of a precipitate forming. After cooling the precipitate is filtered err and the filtrate is evaporated under reduced pressure. The residue is chromatographed on g. of acid-washed silica gel, with fractions of 5 ml. each being taken. Elution is carried out with ml. of benzene, 30 ml. of a 921-, 25 ml. of a 4: 1- and 10 ml. of a lzl-mixture of benzene and ethyl acetate and then with 25 ml. of ethyl acetate. Fractions 2-6 yield a rhodium complex having a strong CO absorption at 5.18;. in the infra-red spectrum. A small quantity of 1 formyl 2u-isopropenyl-mercapto3a-(N- phenyloxyacetyl-amino)-azetidin-4-one can, be isolated from fractions 1 0-12, While from the fractions l7 the 2u-isopropenylmercapto-3a-(N-phenyloxyacetyl amino)- azetidin-4-one of the formula is obtained as an amorphous product. The product can be obtained in crystalline form when the eluate is filtered through 0.5 g. of acid-Washed silica gel and Washed out with a lzl-mixture of benzene and ethyl acetate, M.P. 156158; [a] =70 i2 (c.=0.665 in chloroform); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.07;/., 5.65;, 5.96;.t, 6.29 6.59;/., 6.74 8.19 9.25; and 9.92;.

EXAMPLE 22 A solution of 0.35 g. of the crude l-formyl-h-isopropenyl-mercapto-3u-(N-phenyloxyacetyl-amino) azetidin- 4-one, resulting from the process of Example 18, in 7.5 ml. of tetrahydrofuran, is cooled to 15, diluted with 7.5 ml. of methanol and treated dropwise over the course of 1 hour with 1 ml. of a 0.1 N aqueous sodium hydroxide solution. The reaction mixture is stirred for minutes at l5 and is then diluted with 100 ml. of methylene chloride and washed with water; the aqueous solution is backwashed with methylene chloride. The combined organic solutions are dried and evaporated under reduced pressure. The residue is crystallized from benzene; the 2a-isopropenylmercapto-3a-(N-phenyloxyacetyl-amino) azetidin-4-one thus obtained melts at 157-158" after recrystallization from a mixture of methylene chloride and ether.

The residue from the mother liquors is chromatographed on 5 g. of acid-washed silica gel; apolar by-p-roducts are eluted with 20 ml. of benzene, 60 ml. of a 9:1- mixture of benzene and ethyl acetate and 50 ml. of a 4: 1- mixture of benzene and ethyl acetate, and a further quantity of the 2u-isopropenylmercapto-3a-(N-phenyloxyacety1-amino)-azetidin-4-one is eluted with a further 50 ml. of the same mixture of benzene and ethyl acetate; strongly polar substances are eluted with ethyl acetate.

EXAMPLE 23 The crude product resulting from the process of Example 19 and containing 1-formyl-2u-isopropenylmercapto- 3w(N-phenyloxyacetyl-amino) azetidin 4 one, is dissolved in 45 ml. of methylene chloride, treated with 45 ml. of water and 0.9 ml. of concentrated aqueous ammonia and vigorously stirred at room temperature for 5 hours. The aqueous phase is washed twice with 50 ml. of methylene chloride at a time and the combined organic solutions are dried and evaporated under reduced pressure. The residue is recrystallized from a mixture of methylene chloride and ether and yields the pure 2u-isopropenylmercapto-3a-(N-phenyloxyacetyl-amino)-azetidin-4-one, M.P. 157-160. The semi-crystalline mother liquor is chromatographed on acid-washed silica gel and yields a further quantity of the desired product.

EXAMPLE 24 The crude 1-formyl-2u-isopropenylmercapto-3a-(N-carbo-tert.-butyloxy-amino)-azetidin-4-one, obtainable resulting from the process of Example 17, is dissolved in 10 m1. of methylene chloride, and the solution is diluted with 10 ml. of water and treated with 10 drops of concentrated aqueous ammonia. The reaction mixture is vigorously stirred for 4 hours at room temperature and is then separated into the two layers; the aqueous phase is washed with methylene chloride and the organic solutions are combined, dried and evaporated. The residue is chromatographed on 15 g. of acid-washed silica gel, elution being carried out with chloroform. Less polar by-products are first eluted in the forerun, and then the desired Zea-ipropenylmercapto 3a (N-carbo-tert.-butyloxy-amino)- azetidin-4-one of the formula is obtained, which after crystallization from cold ether melts at 141 and after sublimation (l28-132/0.001 mm. Hg) at 142-144; [u] =26i1 (c.=0.883 in chloroform); ultraviolet absorption spectrum (in ethanol): :223 mu '(,=4840); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03;t, 5.63;, 5.84;, 6.22;, 6.67u, 7.32;, 7.57;t, 8.64 9.45;1., and 11.65;!"

EXAMPLE 25 A solution of 0.56 g. of the crude 1-forrnyl-2a-isopropenyl-3u-(N-phenyloxyacetyl-amino) azetidin 4 one, resulting from thep rocess of Example 20, in 20 ml. of methylene chloride is mixed with 20 ml. of water and 0.45 ml. of concentrated aqueous ammonia solution and the mixture is vigorously stirred for 4 hours at room temperature. The two layers are separated; the aqueous phase is washed with methylene chloride and the combined organic solutions are dried and evaporated. The crystalline residue is dissolved in chloroform and filtered through 4 g. of acid-washed silica gel, whereupon an apolar yellow fraction is first obtained, followed, on eluting with chloroform, by the pure crystalline 2a-isopropenyl-3u-(N-phenyl-amino)-azetidin-4-one, M.P. 157-158. The yellow fraction is chromatographed on 10 g. of acid-washed silica gel, elution being carried out with chloroform; after non-polar impurities, a further quantity of the desired product can thus be obtained.

EXAMPLE 26 Half of the crude product, obtainable according. to the process of Example 7, containing 2u-(2-acetyloxy-2-propyl-mercapto)-3a-(N-phenyloxyacetyl amino) azetidin- 4-one, is dissolved in 5 ml. of anhydrous dioxane and the solution is kept for 17 hours at and then evaporated under reduced pressure. The crude product is chromatographed on 1 g. of acid-washed silica gel. Apolar by-prodnets are eluted with 10 ml. of benzene and 20 ml. of a 9: l-mixture of benzene and ethyl acetate, and the crystalline 2a-isopropenylmercapto 3oz (N-phenyloxyacetylamino)-az etidin-4-one is eluted with 30 ml. of a 4: l-mixture of benzene and ethyl acetate, M. P. .156-158".

In a similar manner, 2m-isopropenylrnercapto-3u-(N- carbo-tert.-butyloxy-amino)-azetidin-4one is obtained on heating 2a-(2-acetyloxy-2-propylmercapto)-3a-(N-carbotert.-butyloxy-amino)-azetidin-4-one.

EXAMPLE 27 is eluted with a 4:1-mixture of benzene and ethyl acetate. 30% of the resulting product is starting material; the infrared absorption spectrum (in methylene chloride) shows characteristic bands at 3.04,u, 5.56/.L, 5.89,u, 6.26 6.63,u, 6.72 1. and 7.67pm.

EXAMPLE 28 A mixture of 0.5 g. of a 10% palladium-on-charcoal catalyst in ml. of ethyl acetate is pre-hydrogenated at 25, in the course of which 14.3 ml. of hydrogen are taken up. 0.063 g. of 1-formyl-2u-isopropenylmercapto- 3a-(N-phnylacetyl-amine)-azetidin-4-one in 2 ml. of ethyl acetate are then added and the mixture is further hydrogenated for 2 /2 hours at 30. After filtering and evaporating the solvent, the residue is chromatographed on 5 g. of acid-washed silica gel. By-pnoducts are eluted with ml. of benzene and 10 ml. of 4:1-mixture of benzene and ethyl acetate and with a further ml. of the same mixture the l-formyl-2a-isopropylmercapto-3a-(N-phenylacetyl-amino)-azetidin-4-one of the formula O CHa is obtained as a colorless oil which shows characteristic bands at 3.04 5.56;, 5.92;, 6.18 7.24; and 7.68.44, in the infrared absorption spectrum (in methylene chloride).

EXAMPLE 29 melts at 128-130 and 143 (double melting point); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.05 5.63 5.93,n, 6.26;, 6.58 6.70 8.15,u., 9.2l,u and 9.41p..

EXAMPLE 30 A solution of 2a-isopropenylmercapto-3a- (N-carbotert.- butyloxy-amino)-azetidin-4-one in 0.5 ml. of cold trifluoroacetic acid is kept for 15 minutes at 0; the solution turns slightly yellowish and is then diluted with a solution of 1 g. of crystalline sodium acetate in 2 ml. of water. The mixture is extracted three times with 10 ml. of methylene chloride at a time; the combined organic extracts are 26 dried and evaporated under reduced pressure; the acetic acid is removed at 0.001 mm. Hg. The 4,4-dimethy1- azetidino[3.2.0-d]thiazolidin-Z-one of the formula 0=( JI IH Cir-0H HN s \C/ 1130 \CH3 is obtained as a colorless oil which crystallizes on addition of benzene and melts at -117 after recrystallization from benzene; [a] =+8- Ll (c.=0.845 in chloroform); thin layer chromatography (silica gel; system: 1:1- mixture of benzene and ethyl acetate): Rf=0.13; infrared absorption spectrum (in methylene chloride): characteristic bands at 295 5.68; (potassium bromide) and 5.78s.

EXAMPLE 31 A solution of 0.15 g. of 4,4-dimethyl-azetidino[3.2-d] thiazolidin-Z-one in 10 ml. of dry tetrahydrofuran (freshly filtered through a column of aluminum oxide, activity I) is cooled to 0. Phosgene is passed through the cold solution for 5 minutes and the reaction mixture is stirred for a further 30 minutes and with the exclusion of atmospheric moisture; the precipitate which initially appears re-dissolves. The mixture is then evaporated and the residue is chromatographed on 3 g. of acid-washed silica gel. The desired 3-chlorocarbonyl-4,4-dimethyl-azetidino [3.2-d]thiazolidin-2-one of the formula is eluted with benzene and with a 9: l-mixture of benzene and ethyl acetate and crystallizes spontaneously. It is recrystallized from a mixture of benzene and hexane and melts at 178-180 (transformation at l60); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04p., 5.62 5.74p., 7.48 8.28;]. and 11.84,u.

A solution of 0.1 g. of 3-chlorocarbonyl-4,4-dimethylazetidino[3.2-d]thiazolidin-2-one in 10 ml. of tert-butanol is mixed with 0.2 g. of calcium carbonate and heated in a closed vessel for 2 /2 days at 90 bath temperature while stirring. After cooling the mixture is filtered, the residue is washed with benzene and the filtrate is evaporated under reduced pressure. The residue is taken up in benzene; the organic solution is washed with water, dried and again evaporated. The residue is again dissolved in benzene and chromatographed on 1 g. of acid-washed silica gel. The 3-carbotert.-butyloxy-4,4-dimethyl-azetidino[2.2-d1thiazolidin-2-one of the formula is eluted with 9: land 4:1-mixtures of benzene and ethyl acetate and recrystallized from a mixture of ether and pentane, melting point 117-l20 (analytical preparation: 120.5); [a] =274 c.=0.522 in chloroform); thin layer chromatogram (silica gel; system: lzl-mixture of benzene and ethyl acetate): Rf=0.15; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.95,, 5.62;, 5.90,, 7.25,, 7.35 7.75 8.65,, 9.36 10.60;, 11.65; and 12.30;.

27 We claim: 1. A process for the manufacture of compounds of the formula in which Ac represents the acyl radical Ac, with an oxidizing agent furnishing an acyloxy group of the formula -OCOR wherein R is defined as above.

2. A process as claimed in claim 1, wherein oxidizing heavy metal carboxylates are used as oxidants.

3. A process as claimed in claim 2, wherein lead-IV- carboxylates are used.

4. A process as claimed in claim 3, wherein lead tetraacetate is used.

5. A compound of the formula O=C--N-OHO in which Ac is a member selected from the group consisting of lower alkanoyl having up to 8 carbon atoms, lower alkenoyl having up to 8 carbon atoms, phenylacetyl, phenyloxyacetyl, caro-lower alkoxy, carbo-adamantyloxy, carbo-phenyl-lower alkoxy and carbo-furyl-lower alkoxy, each of said lower alkoxy moieties having 1 to 7 carbon atoms, and R is a member selected from the group consisting of lower alkyl having 1 to 7 carbon atoms and phenyl.

6. A compound as claimed in claim 5 and being 1- formyl 20c (2 acetyloxy-Z-propylmercapto)-3a-(N- phenyloxy-acetyl-amino -azetidine-4-one.

7. A compound as claimed in claim 5 and being 1- formyl 20c (2 acetyloxy-Z-propyl-mercapto)-3a-(N- phenylacetyl-amino)-azetidine-4-one.

8. A compound as claimed in claim 5 and being 1- formyl 2a (2 acetyloxy-Z-propyl-mercapto)-3a-(N- carbo-tert.-butyloxy-amino)-azetidine-4-one.

9. A compound as claimed in claim 5 and being 1- formyl 2a (2 benzoyloxy-2-propyl-mercapto) 3oc-(N- phenyloxy-acetyl-amino) -azetidine-4-one.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner US. Cl. X.R. 

